Benzoxazines for use in the treatment of parkinson&#39;s disease

ABSTRACT

Benzoxazines of Formula (I) wherein R 1  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or (CH 2 ) n  phenyl, R 2  is C 3 -C 6  alkyl, R 3  is hydrogen, halo, hydroxy, alkoxy, or alkylthio, R 4  is hydrogen or alkyl, or a pharmaceutically acceptable salt thereof, are useful for treating movement disorders such as Parkinson&#39;s disease.

FIELD OF THE INVENTION

[0001] This invention relates to treatment of movement disorders such asParkinson's disease using certain benzoxazine compounds.

BACKGROUND OF THE INVENTION

[0002] Movement disorders are progressive neurodegenerative diseasescharacterized by hypokinesia, tremor, and muscular rigidity. One of themost common movement disorders is Parkinson's disease (PD). It resultsin a slowing of voluntary movements, a festinating gait, peculiarposture, and general weakness of muscles. There is progressivedegeneration within the nuclear masses of the extrapyramidal system, anda characteristic loss of melanin-containing cells from the substantianigra and a corresponding reduction in dopamine levels in the corpusstriatum. The cause of PD is unknown, but it is widely believed thatmultifactorial genetic and environmental factors are contributors. Whilethe disease can develop at any age, it is most common in adults, andtypically afflicts people at about sixty years of age and older.Parkinson's disease is becoming a particularly serious disease given theaging population.

[0003] There are no known cures for movement disorders such as PD. Themost common treatment has been the administration of levodopa, theprecursor to dopamine, whose concentration in the substantia nigra isknown to diminish as the disease progresses. Levodopa often producesunpleasant complications, resulting in even more serious health problemsthat are untreatable.

[0004] There are a group of monomeric proteins called muscarinicreceptors found throughout the body of animals, including humans. Thesemuscarinic receptors are present in the central nervous system, theperipheral nervous system, and in peripheral organs. There have now beenfive muscarinic receptor subtypes identified, and they are referred toas M₁, M₂, M₃, M₄, and M₅ receptors. These various receptors are presentthroughout the body, and the individual subtypes seem to be responsiblefor different actions. For example, in peripheral tissues, M₁ receptorsamplify ganglionic neurotransmission. M₂ receptors cause reducedcontractility and heart rate, while M₃ receptors cause contraction ofsmooth muscles. For muscarinic receptors in brain tissue, the M₁receptors are responsible for memory and learning, the M₂ receptors areresponsible for control of autonomic functions, and the M₄ receptorscontrol motor behavior.

[0005] Compounds that antagonize muscarinic receptors have beendeveloped for treatment of neurodegenerative diseases and movementdisorders such as PD. Because the various muscarinic receptor subtypesare expressed in numerous body tissues, and each subtype appears tocontrol or effect a different bodily function, it would be useful tofind compounds that are selective for a single subtype. The M₄ subtypeis found in high levels in the striatum of the brain and is responsiblefor motor function. Accordingly, compounds that selectively antagonizethe M₄ receptor would be useful as treatments for movement disorderssuch as PD, without adversely affecting other body functions controlledby the other muscarinic receptor subtypes.

[0006] Augelli-Szafiam et al., describe a series of benzoxazines thatare said to be M4 selective muscarinic antagonists (Bioorg. Med. Chem.Lett. 8,1998;1991-1996). The compounds permit only hydrogen and methylat the 2-position. We have now found a group of benzoxazine compoundshaving longer chain alkyl groups at the 2-position that are surprisinglypotent and selective antagonists at the M₄ receptor. An object of thisinvention is to provide the compounds as new chemical entities, and amethod for treating movement disorders utilizing such compounds.

SUMMARY OF THE INVENTION

[0007] This invention provides certain benzoxazine compounds,pharmaceutical compositions comprising them, and a method for treatingmovement disorders by administering them. More particularly, theinvention is a benzoxazine of Formula I

[0008] or a pharmaceutically acceptable salt thereof, wherein:

[0009] R¹ is C₁-C₆ allyl, C₂-C₆ alkenyl, or (CH2)_(n) phenyl;

[0010] R² is C₃-C₆ alkyl;

[0011] R³ is hydrogen, halo, hydroxy, O—C₁-C₆ alkyl, or S—C₁-C₆ alkyl;

[0012] R⁴ is hydrogen, C₁-C₆ alkyl, or (CH₂)_(n) phenyl; and

[0013] n is an integer from 0 to 3.

[0014] Preferred compounds have Formula I wherein R² is n-propyl.

[0015] Also preferred are compounds of Formula I wherein R¹ is ethyl.

[0016] The most preferred compounds have Formula I wherein R¹ is ethyl,R² is n-propyl, R⁴ is hydrogen or methyl, and R³ is OCH₃ or SCH₃.

[0017] Another embodiment of the invention is a pharmaceuticalcomposition comprising a compound of Formula I together with apharmaceutically acceptable diluent, excipient, or carrier therefor.

[0018] Another embodiment is a method for treating movement disorderssuch as Parkinson's disease comprising administering to a patient inneed of treatment a compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

[0019] As used herein, the tenn C₁-C₆ alkyl means straight and branchedhydrocarbon chains having from 1 to 6 carbon atoms. Examples includemethyl, ethyl, isopropyl, n-butyl, 1,1-dimethylbutyl, isohexyl, andneopentyl. “C₃-C₆ alkyl” means straight and branched hydrocarbon chainshaving from 3 to 6 carbon atoms, groups such as n-propyl, isopropyl,n-butyl, n-pentyl, isopentyl, and n-hexyl.

[0020] The term “O—C₁-C₆ alkyl” means the foregoing C₁-C₆ alkyl groupslinked through an oxygen atom. Typical groups are methoxy, ethoxy,isopropoxy, tert-butoxy, n-pentyloxy, and n-hexyloxy. Similarly,“S—C₁-C₆ alkyl” means a C₁-C₆ alkyl group bonded through a sulfur atom.Examples include thiomethyl, thioethyl, thio-n-butyl, and thio-n-hexyl.

[0021] “C₂-C₆ alkenyl” means straight or branched alkyl groups having adouble bond in the chain. Examples include ethenyl, 2-propenyl,2-butenyl, 3-butenyl, 1-methyl-3-butenyl, and 3-hexanyl.

[0022] The group “(CH₂)_(n)-phenyl” includes benzyl, 2-phenylethyl, and3-phenylpropyl.

[0023] The alkyl, alkenyl, and phenyl groups can be substituted with upto three groups such as hydroxy, alkoxy, halo, amino, alkylamino, anddialkylamino. Examples include chloromethyl, methoxymethyl,2-hydroxyethyl, 4-amino-2-butenyl, 3,4-dibromobenzyl,3,4,5-trimethoxybenzyl, and the like.

[0024] The term “movement disorders” as used herein means neurologicaldiseases that are manifested in uncontrolled body motions. Typicalmovement disorders include ataxia, tardive dyskinesia, Tourette'ssyndrome, Wilson disease, dystonia, writer's cramp, essential tremor,Huntington's disease, multiple system atrophy, myoclonus, Parkinson'sdisease, progressive supranuclear palsy, restless leg syndrome, Rettsyndrome, spasticity due to stroke, cerebral palsy, multiple sclerosis,spinal cord or brain injury.

[0025] “Patient” means a mammal, and includes humans, dogs, cats,horses, cattle, and sheep.

[0026] “Effective amount” means the quantity of a compound of Formula Irequired to treat the movement disorder being suffered by the patient.

[0027] “Halo” means fluoro, chloro, bromo, or iodo.

[0028] The compounds of Formula I can exist aspharmaceutically-acceptable salts. The term “pharmaceutically acceptablesalt” as used herein refers to the addition salts of the compounds ofthe present invention which are, within the scope of sound medicaljudgement, suitable for use in contact with the tissues of patientswithout undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the invention. The term “salts” refers to therelatively nontoxic, inorganic, and organic acid addition salts ofcompounds of the present invention. These salts can be prepared in situduring the final isolation and purification of the compounds or byseparately reacting the purified compound in its free base form with asuitable organic or inorganic acid and isolating the salt thus formed.Representative salts include the hydrobromide, hydrochloride, sulfate,bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate,stearate, laurate, borate, benzoate, lactate, phosphate, tosylate,citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate,glucoheptonate, lactiobionate and laurylsulphonate salts, and the like.Invention salts include cations based on the alkali and alkaline earthmetals such as sodium, lithium, potassium, calcium, magnesium, and thelike, as well as, nontoxic ammonium, quaternary ammonium and aminecations including, but not limited to ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylarnine, trimethylamine,triethylamine, ethylamine, and the like. (See, for example, Berge S. M.et al., Pharmaceutical Salts, J. Pharm. Sci., 1977;66:1-19 which isincorporated herein by reference.)

[0029] In addition, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention. Some of the compounds may have chiral centers,and this invention includes all racemates and individual enantiomers, aswell as all geometric isomers.

[0030] The compounds of Formula I are readily prepared by methodsutilizing standard organic chemical reactions. The starting materialsare available from commercial sources or can be prepared from commonreactants using standard methodologies. A typical synthesis of inventioncompounds of Formula I is illustrated in Scheme 1, in which a5-hydroxy-4-dimethylamino indole is coupled with a dihydroisoquinoline.These reactants undergo a Diels-Alder condensation to provide desiredbenzoxazines of Formula I.

[0031] The indole Mannich base and dihydroisoquinoline generally aremixed in a neutral solvent such as dioxane, and the solution generallyis stirred for about 2 to 6 hours at elevated temperatures of about 80°C. to about 150° C. The product benzoxazine is readily isolated byremoval of the reaction solvents, and it can be further purified ifdesired by crystallization, chromatography, salt formation, and thelike.

[0032] The reactants required to prepare benzoxazines according toScheme 1 are either commercially available or are readily prepared bystandard methods. The isoquinolines are prepared according to Schemes 2and 3, and the indole Mannich base is prepared according to Scheme 4.

[0033] Scheme 2 illustrates the synthesis of6-methoxy-3,4-dihydro-isoquinoline (III). The condensation reaction ofN-[2-(3-methoxy-phenyl)-ethyl]-formamide (I) with formic acid isfollowed by Bischler-Napieralski ring closure.

[0034] Scheme 3 depicts the synthesis of6-methylsulfanyl-3,4-dihydro-isoquinoline (XII). 3-Amino-benzoic acid(IV) is diazotized, reacted with sodium ethyl xanthate, followed bysaponification, and is alkylated with dimethyl sulfate to give3-methylsulfanyl-benzoic acid (V). This acid is reduced with Red-Al®(sodium bis (2-methoxyethoxy) aluminum hydride in toluene, Aldrich,Milwaukee, Wis., USA) to yield the alcohol (VI) which is converted to abenzyl chloride (VII) using thionyl chloride. The benzyl nitrilecompound (VIII) is synthesized by treating (VII) with potassium cyanidein the presence of 18-crown-6. Standard reduction conditions (e.g.,Raney nickel) gives phenethyl carbamate (IX), and deprotection yieldsthe phenethylamine (X). (XI) is obtained by treating (X) with ethylformate, followed by ring closure using phosphorus oxychloride to givethe desired dihydroisoquinoline (XII).

[0035] Scheme 4 illustrates the condensation conditions of a ketoester(XIII) and a substituted amine (R³NH₂) to yield the ene amino ester(XIV), which is then used for the Nenitzescu reaction to give asubstituted 5-hydroxy-indole (XV). Standard Mannich reaction conditionsaffords the Mannich base (XVI).

[0036] It may be desirable to use protecting groups for exposedfunctional groups during synthesis of intermediates and inventioncompounds. The use of protecting groups on hydroxy, amino, andcarboxylic acid functional groups is common in organic syntheticmethodologies so as to avoid unwanted side reactions during a particularchemical conversion. The use of protecting groups is fully described byGreene and Wuts in Protecting Groups in Organic Synthesis, (John Wiley &Sons Press, 2 ^(nd) ed), which is incorporated herein by reference.Typical hydroxy protecting groups include ester forming groups such asformyl and acetyl. Amines generally are protected with acyl groups suchas acetyl, benzoyl, or tert.-butoxycarbonyl (BOC), and with groups suchas trimethylsilyl or benzyl. Carboxylic acids generally are protected byesterification with groups such as 2,2,2-trichloroethyl and benzyl. Allsuch protecting groups are readily removed by standard methods.

[0037] The following detailed examples illustrate the synthesis ofspecific invention compounds of Formula I. The examples are provided byway of illustration only, and are not to be construed as limiting theinvention in any respect. The compounds will be named as substituteddiazabenzo[a]cyclopent[h]anthracenes by reference to the numbering shownin the following formula:

EXAMPLE 1

[0038]9-Methoxy-2-propyl-11,12-dihydro-3H,6αH,13H-6-oxa-3,12α-diaza-benzo[a]cyclopent[h]anthracene-1-carboxylicacid ethyl ester

[0039] Preparation of N-[2-(3-methoxy-phenyl)-ethyl]-formamide (Step A,Scheme 2)

[0040] A solution of 2-(3-methoxy-phenyl)-ethylamine (50.0 g, 0.33 mol)in formic acid (60 mL) was refluxed overnight. Water (250 mL) was addedand the emulsion extracted with ethyl acetate (2×150 mL). The organiclayer was separated, died (Na₂SO₄) and concentrated to giveN-[2-(3-methoxy-phenyl)-ethyl]-formamide (43.1 g, 73%). MS: 180.1(M⁺1⁺).

[0041] Preparation of 6-Methoxy-3,4-dihydro-isoquinoline (Step B, Scheme2)

[0042] Phosphorus oxychloride (80 mL, 0.85 mol) was added dropwise toN-[2-(3-methoxy-phenyl)-ethyl]-formamide (41.1 g, 0.24 mol) and refluxedfor 1 hour. The reaction mixture was cooled to room temperature, andhexane (3×500 mL) was added and decanted off three times. To the darkoily solution was added slowly water (200 mL) while stirring. Themixture was basified with NaOH to pH >13, extracted with ethyl acetate,dried (Na₂SO₄) and concentrated to afford the desired product (26.1 g,67%). MS: 162.1 (M⁺1⁺).

[0043] Preparation of 5-Hydroxy-2-propyl-1H-indole-3-carboxylic acidethyl ester (Step A, B, Scheme 4).

[0044] Through a solution of ethyl butyrylacetate (23 g, 0.145 mol) inmethanol (200 mL) was bubbled ammonia at 5° C. for 15 minutes and thenstirred at room temperature for 24 hours. The reaction mixture wasconcentrated to about 20 mL. Acetic acid (150 mL) and 1,4-benzoquinone(15.7 g, 0.145 mol) was added to the reaction mixture and it was stirredfor 3 hours at room temperature. The suspension that formed wasfiltered, washed with CH₂Cl₂ (2×50 mL), and the solid residue was driedin a vacuum oven at 50° C. for 24 hours to give the desired product (2.2g, 6%). MS: 248.1 (M⁺1⁺).

[0045] Preparation of4-(Dimethyl-aminomethyl)-5-hydroxy-2-propyl-1H-indole-3-carboxylic acidethyl ester (Step C, Scheme 4)

[0046] To solution of 5-hydroxy-2-propyl-1H-indole-3-carboxylic acidethyl ester (2.2 g, 8.9 mmol) in ethanol (20 mL) was added formaldehyde37% (0.85 mL, 10.7 mmol) and dimethylamine 40% (2.2 mL, 19.6 mmol). Thereaction mixture was stored at 50° C. overnight, diluted with water (200mL), and extracted with CH₂Cl₂ (3×50 mL). While adding HCl 7% solidmaterial precipitated. The water layer was filtered and the solidresidue basified with K₂CO₃ 10%, extracted with CH₂Cl₂ (3×50 mL), dried(Na₂SO₄) and concentrated to give the desired product (1.2 g, 44%). MS:305.1 (M⁺1⁺).

[0047] Preparation of9-Methoxy-2-propyl-11,12-dihydro-3H,6αH,13H-6-oxa-3,12α-diaza-benzo[a]cyclopent[h]anthracene-1-carboxylicacid ethyl ester (Scheme 1).

[0048]4-(Dimethyl-aminomethyl)-5-hydroxy-2-propyl-1H-indole-3-carboxylic acidethyl ester (1.4 g, 4.6 mmol) and 6-methoxy-3,4-dihydro-isoquinoline(0.74 g, 4.6 mmol) were refluxed in Dioxane (20 mL) for 4 hours under astream of nitrogen. The solution was concentrated and chromatographedwith CH₂Cl₂/methanol to give the desired product (0.05 g, 5%). mp191-193° C.

[0049] MS: 421.2 (M⁺1⁺).

[0050] Analysis for C₂₅H₂₈N₂O₄0.11H₂O: Calcd: C, 71.07; H, 6.73; N,6.63.

[0051] Found: C, 70.69; H, 6.73; N, 6.50.

EXAMPLE 2

[0052]3-Methyl-9-methylsulfanyl-2-propyl-11,12-dihydro-3H,6aH,13H-6-oxa-3,12a-diaza-benzo[a]cyclopent[h]anthracene-1-carboxylicacid ethyl ester

[0053] Preparation of 3-Methylsulfanyl-benzoic acid (Step A, Scheme 3)

[0054] The aminobenzoic acid (54.8 g, 0.4 mol) was diazotized in theusual manner with sodium nitrite (27.6 g, 0.4 mol) and hydrochloric acid(40 mL) and the resulting diazonium salt solution poured into a hot (70°C.), freshly prepared solution of potassium ethyl xanthate (64.2 g, 0.4mol) containing sodium carbonate (55.2 g, 0.4 mol) to neutralize acid inthe diazonium salt solution. After the reaction was over, as indicatedby the cessation of the evolution of gases, the mixture was cooled. Itwas then treated with potassium hydroxide (24.7 g, 0.44 mol) anddimethyl sulfate (50.4 g, 0.4 mol). The mixture was refluxed for 5hours. On acidification with hydrochloric acid, the desired product wasobtained (38.2 g, 57%). MS: 167.8 (M⁺1⁺).

[0055] Preparation of (3-Methylsulfanyl-phenyl)-methanol (Step B, Scheme3)

[0056] To a suspension of 3-methylsulfanyl-benzoic acid (38 g, 0.226mol) in Toluene (500 mL) was added 200 mL of Red-AID® dropwise at 50° C.over 30 minutes. After stirring at room temperature for 3 hours, NaOH10% (250 mL) was added while cooling with an ice-bath and then stirredovernight. The organic layer was separated and the water layer extractedtwice with toluene (2×100 mL). The combined organic layers were dried(K₂CO₃), concentrated and distilled under reduced pressure to give thedesired product (23.8 g, 68%). MS: 152.7 (M⁺1³¹ ).

[0057] Preparation of 1-Chloromethyl-3-methylsulfanyl-benzene (Step C,Scheme 3)

[0058] To a solution of (3-methylsulfanyl-phenyl)-methanol (23.8 g,0.156 mol) in benzene (250 mL) was added thionyl chloride (26.9 g, 0.234mol) under cooling with an ice-bath. The ice-bath was removed and thereaction mixture stirred for 48 hours at room temperature. The solutionwas concentrated and used without further work-up (26.9 g).

[0059] Preparation of (3-Methylsulfanyl-phenyl)-acetonitrile (Step D,Scheme 3)

[0060] To a solution of 1-chloromethyl-3-methylsulfanyl-benzene (26.9 g,0.156 mol) and 18-crown-6 (2 g, 7.8 mmol) in dry acetonitrile (100 mL)was added potassium cyanide and stirred at room temperature for 48hours. A precipitate was formed while adding dichloromethane (400 mL).The suspension was filtered, washed with water (2×150 mL), dried(Na₂SO₄) concentrated and distilled under reduced pressure to give acolorless oil (22.9 g, 91%).

[0061] MS: 161.9 (M⁺1⁻).

[0062] Preparation of (3-Methylsulfanyl-phenyl)-ethyl]carbolic acidtert-butyl ester (Step E, Scheme 3)

[0063] To a solution of (3-methylsulfanyl-phenyl)-acetonitrile (22.9 g,0.14 mol) and BOC anhydride. (47 g, 0.25 mol) in methanol (200 mL) wasadded Raney nickel (18 g). The mixture was shaken at room temperaturefor 48 hours. The mixture was filtered and concentrated. Chromatographywith hexane/ethyl acetate gave the desired product (12 g, 33%). MS:268.0 (M⁺1⁺).

[0064] Preparation of 2-(3-Methylsulfanyl-phenyl)-ethylamine (Step F,Scheme 3)

[0065] To a solution of (3-methylsulfanyl-phenyl)-ethyl]carbolic acidtert-butyl ester (12 g, 45 mmol) in CH₂Cl₂ (60 mL) was addedtrifluoroacetic acid (40 mL) and stirred for 10 minutes at roomtemperature. After the reaction was over, as indicated by the cessationof the evolution of gases, sodium hydroxide was added portionwise topH>13. The emulsion was extracted with CH₂Cl₂ (3×100 mL), dried (MgSO₄),and concentrated to give an orange oil (7.4 g, 99%). MS: 167.9 (M⁺1⁺).

[0066] Preparation of N-[2-(3-Methylsulfanyl-phenyl)-ethyl]-formamide(Step G, Scheme 3)

[0067] A procedure identical to that described for the preparation ofN-[2-(3-methoxy-phenyl)-ethyl]-formamide in Example 1 was followed using2-(3-methylsulfanyl-phenyl)-ethylamine (7.4 g, 44 mmol) and formic acidethyl ester (3.6 g, 48 mmol) to give the desired product (6.7 g, 78%).MS: 168.9 (M⁺1⁺).

[0068] Preparation of 6-Methylsulfanyl-3,4-dihydro-isoquinoline (Step H,Scheme 3)

[0069] A procedure identical to that described for the preparation ofN-[2-(3-methoxy-phenyl)-ethyl]-formamide in Example 1 was followed usingN-[2-(3-methylsulfanyl-phenyl)-ethyl]-formamide (6.7 g, 34 mmol) to givethe desired product (0.8 g, 13%). MS: 178.1 (M⁺1⁺).

[0070] Preparation of 5-Hydroxy-1-methyl-2-propyl-1H-indole-3-carboxylicacid ethyl ester (Step A, B, Scheme 4)

[0071] A procedure identical to that described for the preparation of5-hydroxy-2-propyl-1H-indole-3-carboxylic acid ester in Example 1 wasfollowed using methylamine to give the desired product (6.1 g, 39%). MS:262 (M⁺1⁺).

[0072] Preparation of3-Methyl-9-methylsulfanyl-2-propyl-11,12-dihydro-3H,6aH,13H-6-oxa-3,12a-diaza-benzo[a]cyclopent[h]anthracene-1-carboxylicacid ethyl ester (Scheme 1)

[0073] A procedure identical to that described for the preparation of9-methoxy-2-propyl-11,12-dihydro-3H,6αH,13H-6-oxa-3,12α-diaza-benzo[a]cyclopent[h]-anthracene-1-carboxylicacid ethyl ester in Example 1 was followed to react4-(dimethylaminomethyl)-5-hydroxy-2-propyl-1H-indole-3-carboxylic acidethyl ester with 6-methylsulfanyl-3,4-dihydro-isoquinoline (0.8 g, 4.5mmol) to give the desired product (0.035 g, 2%). mp 139-143° C. MS:451.1 (M⁺1⁺).

[0074] Analysis for C₂₆H₃₀N₂O₃S0.27H₂O: Calcd: C, 68.56; H, 6.76; N,6.15.

[0075] Found: C, 68.19; H, 6.67; N, 6.02.

EXAMPLE 3

[0076]9-Methoxy-3-methyl-2-propyl-11,12-dihydro-3H,6aH,13H-6-oxa-3,12a-diaza-benzo[a]cyclopent[h]anthracene-1-carboxylicacid ethyl ester

[0077] Preparation of9-Methoxy-3-methyl-2-propyl-11,12-dihydro-3H,6aH,13H-6-oxa-3,12a-diaza-benzo[a]cyclopent[h]anthracene-1-carboxylic acid ethyl ester(Scheme 1)

[0078] By following the general procedure of Example 2 for thepreparation of9-methoxy-2-propyl-11,12-dihydro-3H,6αH,13H-6-oxa-3,12α-diaza-benzo[a]cyclopent[h]anthracene-1-carboxylicacid ethyl ester,4-(dimethylamino-methyl)-5-hydroxy-1-methyl-2-propyl-1H-indole-3-carboxylicacid ethyl ester (2.1 g, 6.6 mmol) was reacted with6-methoxy-3,4-dihydro-isoquinoline (1.005 g, 6.6 mmol) to give thedesired product (0.22 g, 8%). MP 150-151° C. MS: 435.2 (M⁺1⁺).

[0079] Analysis for C₂₆H₃₀N₂O₄: Calcd: C, 71.87; H, 6.96; N, 6.45.

[0080] Found: C, 71.49; H, 6.89; N, 6.29.

EXAMPLES 4-8

[0081] The following invention compounds were prepared by following thegeneral procedures described above in Examples 1-3.

[0082]9-Methylsulfanyl-2-propyl-11,12-dihydro-3H,6aH,13H-6-oxa-3,12a-diaza-benzo[a]cyclopent[h]anthracene-1-carboxylicacid ethyl ester, mp 185-186° C.;

[0083]2-Butyl-9-methoxy-11,12-dihydro-3H,6aH,13H-6-oxa-3,12a-diaza-benzo[a]cyclopent[h]anthracene-1-carboxylicacid ethyl ester, mp 180-182° C.;

[0084]2-Butyl-9-methylsulfanyl-11,12-dihydro-3H,6aH,13H-6-oxa-3,12a-diaza-benzo[a]cyclopent[h]anthracene-1-carboxylicacid ethyl ester, mp 159-161° C.;

[0085]9-Methoxy-2-pentyl-11,12-dihydro-3H,6aH,13H-6-oxa-3,12a-diaza-benzo[a]cyclopent[h]anthracene-1-carboxylicacid ethyl ester, mp 170-172° C.; and

[0086]2-Hexyl-9-methoxy-11,12-dihydro-3H,6aH,13H-6-oxa-3,12a-diaza-benzo[a]cyclopent[h]anthracene-1-carboxylicacid ethyl ester, mp 157-160° C.

[0087] The compounds of Formula I have shown potent binding affinity formuscarinic receptors and are thus useful as muscarinic antagonists. Thecompounds are surprisingly selective as muscarinic M₄ receptorantagonists. The compounds were evaluated in standard assays used tomeasure muscarinic receptor binding, and they were compared with otherbenzoxazines described in Bioorganic & Medicinal Chemistry Letters 8,1998:1991-1996, which is incorporated herein by reference. Specifically,the compounds were evaluated for their binding affinity toward fivehuman muscarinic receptor subtypes (M₁-M₅) by the method of Dorje etal., J. Pharm. Exp. Ther. 1991;256:727-733, which is incorporated hereinby reference. The binding was determined by measuring the displacementof [³H]-NMS (N-methylscopolamine) binding using membranes fromtransfected Chinese hamster ovary (CHO) cells. All compounds were testedtwo to four times with duplicate tubes (SEM is S≦10% in all cases).Table 1 shows the binding activities (IC₅₀ nM) of several prior artcompounds compared to invention compounds. TABLE 1 Muscarinic BindingActivity

Prior Art Compounds R¹ R² R³ R⁴ M₁ M₂ M₃ M₄ M₅ Et Me 9-OMe H 3000 1000500 30 6000 Et Me 9-OMe Me  500  400 400 50 1000 Et Me 9-OMe Et 2000 400 500 50 3000 Et Et 9-OMe H 2000 2000 200 20 6000 Et Et 9-OMe Et 50001000  50 20 5000 Invention Compounds Ex- am- ple No. R¹ R² R³ R⁴ M₁ M₂M₃ M₄ M₅ 1 Et nPr 9-OMe H 4660 2000 130 9 3660 2 Et nPr 9-SMe Me 75007000 370 7 3000 3 Et nPr 9-OMe Me 3000 950 130 7 6000 4 Et nPr 9-SMe H1400 2000 200 6 3500 5 Et nBu 9-OMe H 800 550 190 6 13000 6 Et nBu 9-SMeH 2000 4000 5000 10 2000 7 Et n-Pentyl 9-OMe H 50000 600 200 10 10000 8Et n-Hexyl 9-OMe H 2000 800 400 30 3000

[0088] The data in Table 1 establishes that the invention compounds ofFormula I are surprisingly potent and selective for binding to the M₄receptor. “M₄ selective” as used herein means that a compound binds tothe M₄ muscarinic receptor subtype by at least about 20-fold more thanto any of the other receptor subtypes. For example, the inventioncompound of Example 2 binds to the M₄ receptor about 52-fold more thanto M₃, and about 1000-fold more than to M₁, M₂, and M₅. The compounds ofExamples 4 and 5 bind to M₄ by about 30-fold more than to the M₃, and byas much as about 800-fold more than some of the other subtypes. Theprior art compounds are not M₄ selective because they show bindingaffinity of only about 2- to about 15-fold more at M₄ than to any of theother receptors. Because of the potency and M₄ selectivity of theinvention compounds, they are particularly useful for treatment ofmovement disorders such as Parkinson's disease.

[0089] For use in treating movement disorders, the invention compound istypically part of a pharmaceutical composition and is administered to apatient by methods well-known to those skilled in the art. The inventioncompound will be present in an amount of about 5% to about 95% by weightof the composition.

[0090] In the methods of the present invention, a compound can beadministered either orally, rectally, parenterally (intravenous,intramuscularly, or subcutaneously), intracisternally, intravaginally,intraperitoneally, intravesically, locally (powders, ointments, patches,or drops), or as a buccal or nasal spray.

[0091] Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents,solvents, or vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil), and injectable organic esters suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions and by the use of surfactants.

[0092] These compositions may also contain adjuvants such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample, sugars, sodium chloride, and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

[0093] Solid dosage forms for oral administration include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound is admixed with at least one inert customary excipient(or carrier) such as sodium citrate or dicalcium phosphate or (a)fillers or extenders, as for example, starches, lactose, sucrose,glucose, mannitol, and silicic acid; (b) binders, as for example,carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone,sucrose, and acacia; (c) humectants, as for example, glycerol; (d)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, certain complex silicates, andsodium carbonate; (e) solution retarders, as for example, paraffin; (f)absorption accelerators, as for example, quaternary ammonium compounds;(g) wetting agents, as for example, cetyl alcohol and glycerolmonostearate; (h) adsorbents, as for example, kaolin and bentonite; and(i) lubricants, as for example, talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, or mixturesthereof. In the case of capsules, tablets, and pills, the dosage formsmay also comprise buffering agents.

[0094] Solid compositions of a similar type may also be employed asfillers in soft- and hard-filled gelatin capsules using such excipientsas lactose or milk sugar, as well as high molecular weightpolyethyleneglycols, and the like.

[0095] Solid dosage forms such as tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells, such as entericcoatings and others well-known in the art. They may contain opacifyingagents, and can also be of such composition that they release the activecompound or compounds in a certain part of the intestinal tract in adelayed manner. Examples of embedding compositions which can be used arepolymeric substances and waxes. The active compounds can also be inmicroencapsulated form, if appropriate, with one or more of theabove-mentioned excipients.

[0096] Liquid dosage forms for oral administration includepharmaceutically acceptable emulsions, solutions,;suspensions, syrups,and elixirs. In addition to the active compounds, the liquid dosageforms may contain inert diluents commonly used in the art, such as wateror other solvents, solubilizing agents and emulsifiers, as for example,ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,dimethylformamide, oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil, and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid estersof sorbitan or mixtures of these substances, and the like.

[0097] Besides such inert diluents, the composition can also includeadjuvants, such as wetting agents, emulsifying and suspending agents,sweetening, flavoring, and perfuming agents.

[0098] Suspensions, in addition to the active compounds, may containsuspending agents, as for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth,or mixtures of these substances, and the like.

[0099] Compositions for rectal administrations are preferablysuppositories which can be prepared by mixing the compounds of thepresent invention with suitable nonirritating excipients or carrierssuch as cocoa butter, polyethyleneglycol or a suppository wax, which aresolid at ordinary temperatures but liquid at body temperature andtherefore, melt in the rectum or vaginal cavity and release the activecomponent.

[0100] Dosage forms for topical administration of a compound of thisinvention include ointments, powders, sprays, and inhalants. The activecomponent is admixed under sterile conditions with a physiologicallyacceptable carrier and any preservatives, buffers or propellants as maybe required. Ophthalmic formulations, eye ointments, powders, andsolutions are also contemplated as being within the scope of thisinvention. Controlled release compositions in the form of skin patchesand the like also are provided.

[0101] Typical doses of invention compounds will be from about 0.1 toabout 1000 mg/kg, and generally from about 5 to about 250 mg/kg. Suchdoses can be administered from one to about four times each day, or asoften as an attending physician may direct.

[0102] The following examples illustrate typical compositions providedby this invention. Tablet Formulation Ingredient Amount Compound ofExample 1  50 mg Lactose  80 mg Cornstarch (for mix)  10 mg Cornstarch(for paste)  8 mg Magnesium Stearate (1%)  2 mg 150 mg

[0103] The compound of Example 1 is mixed with the lactose andcornstarch (for mix) and blended to uniformity to a powder. Thecornstarch (for paste) is suspended in 6 mL of water and heated withstirring to form a paste. The paste is added to the mixed powder, andthe mixture is granulated. The wet granules are passed through a No. 8hard screen and dried at 50° C. The mixture is lubricated with 1%magnesium sterate and compressed into a tablet. The tablets areadministered to a patient at the rate of 1 to 4 each day for treatmentof Parkinson's disease and other movement disorders.

EXAMPLE 10

[0104] Parenteral Solution

[0105] In a solution of 700 mL of propylene glycol and 200 mL of waterfor injection is added 20.0 g of the compound of Example 2. The mixtureis stirred, and the pH is adjusted to 5.5 with hydrochloric acid. Thevolume is adjusted to 1000 mL with water for injection. The solution issterilized, filled into 5.0 mL ampoules, each containing 2.0 mL (40 mgof Example 2), and sealed under nitrogen. The solution is administeredby injection to a patient suffering from Parkinson's disease or othermovement disorder and in need of treatment.

EXAMPLE 11

[0106] Patch Formulation

[0107] Ten milligrams of9-methoxy-3-methyl-2-propyl-11,12-dihydro-3H,6aH,13H-6-oxa-3,12a-diaza-benzo[a]cyclopent[h]anthracene-1-carboxylicacid ethyl ester is mixed with 1 mL of propylene glycol and 2 mg ofacrylic-based polymer adhesive containing a resinous cross-linkingagent. The mixture is applied to an impermeable backing (30 cm²) andapplied to the upper back of a patient for sustained release treatmentof Parkinson's disease or other movement disorder.

[0108] A further embodiment of the invention is a method for treatingmovement disorders comprising administering to a patient suffering froma movement disorder and in need of treatment an effective amount of acompound of Formula I. An “effective amount” is that quantity ofinvention compound that produces a positive clinical reaction in apatient suffering from a movement disorder. An effective amount isgenerally about 0.1 to about 1000 mg/kg. A preferred dosage will be fromabout 1.0 to about 500 mg/kg, and more preferably about 5 to about 250mg/kg. In a preferred embodiment, the invention provides a method fortreating Parkinson's disease comprising administering to a patient aneffective amount of a compound of Formula I.

[0109] The invention and the manner and process of making and using it,are now described in such full, clear, concise, and exact terms as toenable any person skilled in the art to which it pertains, to make anduse the same. It is to be understood that the foregoing describespreferred embodiments of the present invention and that modificationsmay be made therein without departing from the spirit or scope of thepresent invention as set forth in the claims. To particularly point outand distinctly claim the subject matter regarded as invention, thefollowing claims conclude this specification.

We claim:
 1. A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein: R¹ is C₁-C₆alkyl, C₂-C₆ alkenyl, or (CH₂)_(n)phenyl; R² is C₃-C₆ alkyl; R³ ishydrogen, halo, hydroxy, O—C₁-C₆ alkyl, or S—C₁-C₆ alkyl; R⁴ ishydrogen, C₁-C₆ alkyl, or (CH₂)_(n)phenyl; and n is an integer from 0 to3.
 2. A compound of claim 1 wherein R^(1 i)s ethyl.
 3. A compound ofclaim 2 wherein R² is n-propyl, n-butyl, n-pentyl, or n-hexyl.
 4. Acompound of claim 3 wherein R⁴ is hydrogen or methyl.
 5. The compoundwhich is3-methyl-9-methylsulfanyl-2-propyl-11,12-dihydro-3H,6aH,13H-6-oxa-3,12a-diaza-benzo[a]cyclopent[h]anthracene-1-carboxylicacid ethyl ester.
 6. The compound which is9-methoxy-2-propyl-11,12-dihydro-3H,6aH,13H-6-oxa-3,12a-diaza-benzo[a]cyclopent[h]anthracene-1-carboxylicacid ethyl ester.
 7. The compound which is9-methoxy-3-methyl-2-propyl-11,12-dihydro-3H,6aH,13H-6-oxa-3,12a-diaza-benzo[a]cyclopent[h]anthracene-1-carboxylicacid ethyl ester.
 8. A compound selected from the group consisting of9-Methylsulfanyl-2-propyl-11,12-dihydro-3H,6aH,13H-6-oxa-3,12-dihydro-3H,6aH,13H-6-oxa-3,12a-diaza-benzo[a]cyclopent[h]anthracene-1-carboxylicacid ethyl ester;2-Butyl-9-methoxy-11,12-dihydro-3H,6aH,13H-6-oxa-3,12a-diaza-benzo[a]cyclopent[h]anthracene-1-carboxylicacid ethyl ester;2-Butyl-9-methylsulfanyl-11,12-dihydro-3H,6aH,13H-6-oxa-3,12a-diaza-benzo[a]cyclopent[h]anthracene-1-carboxylicacid ethyl ester;9-Methoxy-2-pentyl-11,12-dihydro-3H,6aH,13H-6-oxa-3,12a-diaza-benzo[a]cyclopent[h]anthracene-1-carboxylicacid ethyl ester; and2-Hexyl-9-methoxy-11,12-dihydro-3H,6aH,13H-6-oxa-3,12a-diazo-benzo[a]cyclopent[h]anthracene-1-carboxylicacid ethyl ester.
 9. A pharmaceutical composition comprising a compoundof claim 1 together with a pharmaceutically acceptable diluent,excipient, or carrier therefor.
 10. A method for treating movementdisorders comprising administering to a patient suffering from amovement disorder and in need of treatment an effective amount of acompound of claim
 1. 11. A method according to claim 10 wherein themovement disorder is Parkinson's disease.